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IN THIS ISSUE PD-1 Blockade Is Not Unsafe in Patients with Lung Cancer and COVID-19 • COVID-19 severity and mortality were not • Although PD-1 blockade was not a • This suggests that PD-1 blockade increased in patients with lung cancer risk factor in this population, severity should be used when indicated in patients who received prior PD-1 blockade . and mortality in this group were high . with lung cancer despite COVID-19 . A key issue in oncology of whether patients received the immunotherapy recently or practice during the COVID-19 at any point prior to infection. There was a slight, statistically pandemic is whether PD-1 insignifi cant numeric increase in severity with PD-1 blockade, blockade affects the severity of but controlling for smoking history—which is an expected COVID-19 in patients with can- imbalance in receipt of prior PD-1 blockade and a risk factor cer. PD-1 blockade may increase for severe COVID-19 outcomes—abolished this correlation. COVID-19 severity by contrib- This work suggests that prior PD-1 blockade is not a clinically uting to hyperactive immune meaningful risk factor for worsened COVID-19 outcomes, res ponses to SARS-CoV-2 infec- implying that PD-1 blockade should be used when indicated tion—or, alternatively, may reduce despite the pandemic. Larger studies are needed to more fully severity by enhancing control of initial viral infection. To examine this question. Finally, it should be noted that, in minimize lung cancer as a confounder, Luo and colleagues this study population, more than half of patients with lung assessed the outcomes of concurrent COVID-19 and lung cancer and COVID-19 were hospitalized and almost half of cancer in 69 consecutive patients at a single institution in those hospitalized died, emphasizing the need for studies to New York City. They performed manual annotation, includ- better understand risk factors and the disease course in this ing collecting data from a detailed self-reported smoking sur- group. n vey. PD-1 blockade was not a notable risk factor for increased COVID-19 severity or death among these patients, regardless See article, p. 1121. Anti-EGFR Overcomes KRASG12C-Inhibitor Resistance in Colorectal Cancer • KRASG12C inhibition is effective in some • KRAS G12C-mutant colorectal cancer cells • Inhibition of EGFR plus KRASG12C was KRASG12C-mutant cancers, but not had higher basal activation of the up- effective in colorectal cancer cells and KRASG12C-mutant colorectal cancer . stream receptor tyrosine kinase EGFR . patient-derived organoids and xenografts . Although KRASG12C inhibition of upstream receptor tyrosine kinases, including EGFR. Cor- has shown effi cacy in patients respondingly, treatment of KRASG12C-mutant colorectal cancer with KRASG12C-mutant non– cells with the EGFR inhibitor cetuximab sensitized the cells to small cell lung cancer (NSCLC), AMG510, and cetuximab plus AMG510 treatment inhibited results have been less promis- cell proliferation and was cytotoxic in a colorectal cancer cell ing in patients with KRASG12C- line with acquired resistance (via KRASG12C mutation) to the mutant colorectal cancer. To under- EGFR antibody panitumumab. Extending these fi ndings, com- stand the mechanism underlying bination treatment with cetuximab plus AMG510 exerted syn- KRASG12C-inhibitor resistance in ergistic proliferation suppression in patient-derived organoids KRASG12C-mutant colorectal can- representing KRASG12C-mutant colorectal cancer, and patient- cer, Amodio, Yaeger, Arcella, and colleagues started by testing derived xenograft experiments using tumors from two patients the effects of the KRASG12C inhibitor AMG510 in KRASG12C- with KRASG12C-mutant colorectal cancer demonstrated that mutant NSCLC and colorectal cancer cell lines. This revealed cetuximab plus AMG510 led to marked or even complete that AMG510 treatment did not result in sustained inhibition tumor shrinkage. Together, these results provide insight into of phosphorylation of the downstream kinase ERK in colo- the reason behind the low effi cacy of KRASG12C inhibition in rectal cancer cells—instead, phospho-ERK levels rebounded KRASG12C-mutant colorectal cancer and suggest a therapeutic in colorectal cancer but not NSCLC cells after exposure to strategy that may be useful for overcoming this resistance. n AMG510. Further investigation revealed that the colorectal cancer cells, unlike the NSCLC cells, had high basal activation See article, p. 1129. AUGUST 2020 CANCER DISCOVERY | 1079 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. IN THIS ISSUE Surmountable JAK1/2 and B2M Mutations Confer Anti–PD-1 Resistance • JAK1 , JAK2, or B2M loss-of-function • A TLR9 agonist or an IL2 agonist • Mechanism-informed treatments mutations caused resistance to anti– overcame resistance in JAK1/2- or based on TLR9 or IL2 may be of inter- PD-1 therapy in colon cancer models . B2M-mutant tumors, respectively . est for cancers resistant to anti–PD-1 . Loss-of-function mutations in resistance to anti–PD-1 treatment, with JAK1- and JAK2- JAK1/2 (encoding JAK1 and knockout tumors lacking IFNγ signal amplifi cation, and JAK2, tyrosine kinases involved in B2M-knockout tumors losing surface MHC antigen expres- IFN signaling) and B2M (encod- sion and not being recognized by T cells. In this model, ing β2 microglobulin, a compo- JAK1/2 knockout–induced resistance could be overcome by nent of the MHC class I complex) combining intratumoral TLR9-agonist administration with are implicated in resistance of anti–PD-1 via reactivation of IFN signaling. In the B2M- cancers to anti–PD-1 therapy. To knockout model, resistance could be ameliorated by adding better understand the mecha- the IL2 agonist bempegaldesleukin to anti–PD-1 via natural nisms underlying resistance, killer–mediated responses. Importantly, the TLR9 agonist or Torrejon and colleagues fi rst investigated the effects ofJAK1 , bempegaldesleukin could also alleviate resistance in a mouse JAK2, or B2M knockout in human melanoma cell lines. model of melanoma that exhibits primary resistance to anti– JAK1 or JAK2 knockout caused insensitivity to IFN-mediated PD-1. Together, these results provide further evidence for the cytotoxicity via reduced IFN-induced transcription, whereas role of JAK1/2 and B2M in resistance to anti–PD-1 and sup- B2M knockout did not affect IFN sensitivity but prevented port mechanism-informed therapies that are currently being melanoma cells from being recognized by antigen-specifi c investigated in clinical trials of patients with resistance to T cells due to loss of cell-surface expression of MHC class PD-1 blockade therapy. n I. In a mouse model of colon adenocarcinoma with high mutational burden, JAK1, JAK2, or B2M knockout caused See article, p. 1140. Bempegaldesleukin plus Nivolumab Is Safe in Multiple Malignancies • The IL2 pathway agonist bempegal- • In 38 patients with advanced mela- • Response correlated with higher T-cell desleukin plus anti–PD-1 therapy with noma, renal cell carcinoma, or non–small infiltration and clonality, consistent nivolumab was tested in a phase I trial . cell lung cancer, treatment was safe . with bempegaldesleukin’s mechanism . Although immune-checkpoint 40.5% experienced partial responses, and the median dura- inhibitors produce favorable tion of response was not reached after a median follow-up response rates in several cancers, period of 18 months. Consistent with the proposed mecha- these agents are not always effec- nism for bempegaldesleukin, T-cell infi ltration and clonality tive, perhaps sometimes in part were increased by week three of treatment in tumors that due to low levels of tumor-infi l- responded to the treatment, an observation that warrants trating lymphocytes. Based on further study in larger trials. With regard to safety and toler- evidence that the IL2 pathway ability, all patients experienced at least one treatment-emer- agonist bempegaldesleukin can gent adverse event, most commonly fl u-like symptoms, rash, promote proliferation and acti- fatigue, pruritus, arthralgia, decreased appetite, or headache, vation of CD4+ and CD8+ T cells as well as natural killer cells and there were no treatment-related deaths. Based on the in the tumor microenvironment, Diab, Tannir, Bentebibel, results of this study, the trial has been expanded to include and colleagues conducted a phase I trial of bempegaldesleu- patients with other tumor types; additionally, treatment with kin plus the PD-1 antibody nivolumab in 38 patients with bempegaldesleukin plus nivolumab is now being evaluated in immunotherapy-naïve advanced melanoma, renal cell carci- phase II and III trials including patients with various malig- noma, or non–small cell lung cancer (11, 22, and 5 patients, nancies. n respectively). Among the 37 patients for whom effi cacy evalu- ation was conducted, 18.9% attained complete responses and See article, p. 1158. 1080 | CANCER DISCOVERY AUGUST 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. IN THIS ISSUE Targetable Mutations Occur in CDk4/6 Inhibitor–Resistant Breast Cancer • Genomic alterations in RB1, AURKA, and • These alterations were found in patient • In a phase I trial of an AURKA inhibitor, others correlated with CDK4/6-inhibitor tumors and many occurred with pro- a patient with CDK4/6 inhibitor– resistance in HR+HER2− breast cancer . longed CDK4/6-inhibitor treatment in vitro . resistant disease had a response . CDK4/6

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